Excitatory neurotransmission in the mammalian central nervous system (CNS) is primarily mediated by the amino acid, L-glutamate, acting on ionotropic and metabotropic receptors. The ionotropic receptors, which respond to this amino acid, have been divided into the N-methyl-D-aspartate (NMDA) receptors, the alfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and the kainic acid (KA) receptors. Moreover molecular biological studies have established that these receptors are composed of subunits that can assemble to form functional channels, and a number of such subunits have been identified.
This way it has been established that the AMPA receptors are assembled from four protein subunits known as GluR1 to GluR4, while the KA receptors are assembled from subunits known as GluR5 to GluR7, KA-1 and KA-2.
Due to their distribution in different mammalian tissues, the GluR5 receptors and the substances acting thereon have drawn particular attention.
Thus GB 2316616 describes the use of a compound that modulates the glutamate GluR5 receptor in the hippocampus for the treatment of e.g. cognitive disorders, pain, neurological and psychiatric disorders and for drug screening.
WO 9845270 describes treatment of pain with specific GluR-5 receptor antagonists and new decahydroisoquinoline antagonists of this class.
WO 0102367 describes diester prodrugs of 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, useful for treating pain, with improved bioavailability.
None of these references, however, describe non-competitive, selective GluR5 antagonists or partial agonists, or the use of such compounds.